Recurrence of Hepatocellular Carcinoma After Liver Transplantation: Is There a Place for Resection?

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1 ORIGINAL ARTICLE Recurrence of Hepatocellular Carcinoma After Liver Transplantation: Is There a Place for Resection? Elena Fernandez-Sevilla, 1 Marc-Antoine Allard, 1-3 Jasmijn Selten, 1 Nicolas Golse, 1,2,4 Eric Vibert, 1,2,4 Antonio Sa Cunha, 1,2 Daniel Cherqui, 1,2,4 Denis Castaing, 1,2,4 and Rene Adam Centre Hepatobiliaire, H^opital Paul Brousse, Villejuif, France; 2 Universite Paris-Sud, Villejuif, France; 3 Unite 935, Institut National de la Sante et de la Recherche, Villejuif, France; 4 Unite 785, Institut National de la Sante et de la Recherche, Villejuif, France Recurrence of hepatocellular carcinoma (HCC) after liver transplantation (LT) is widely considered as a terminal condition. Therefore, the role of surgery is uncertain in this case. The purpose of this study was to identify the prognostic factors of survival after post-lt HCC recurrence and to evaluate the impact of surgery in this setting. All patients transplanted for HCC between 1991 and 2013 in a single institution and who further developed a post-lt recurrence were included in this study. Univariate and multivariate analyses were performed to identify factors affecting postrecurrence survival. Of the 493 patients transplanted for HCC, a total of 70 (14.2%) consecutive patients developed a recurrence after a median disease-free interval of 17 months. Median survival (MS) from the time of recurrence was 19 months, with a 3-year postrecurrence survival of 26%. Most recurrences were extrahepatic (lung, lymph node, and bone; n 5 51; 72.9%), whereas only intrahepatic recurrences were observed in 2 (2.8%) patients. Both intrahepatic and extrahepatic locations were found in 17 (24.3%) patients. A total of 22 (31.4%) patients underwent macroscopically complete resection of the recurrence (intrahepatic [n 5 2] and extrahepatic [n 5 20]). The MS for resected patients after transplantation was 35 months compared with 15 months for nonresected patients (P < 0.001). In multivariate analysis, the independent unfavorable factors of postrecurrence survival were alpha-fetoprotein level > 100 ng/ml at relapse (hazard ratio [HR], 2.1; 95% confidence interval [CI], ; P ), intrahepatic location (HR, 1.8; 95% CI, ; P ), and multifocal recurrence (HR, 1.8; 95% CI, ; P ). The management including surgery (HR, 0.4; 95% CI, ; P ) was identified as an independent favorable factor. In conclusion, recurrence of HCC after LT is associated with a poor prognosis. However, resection is associated with improved survival and should therefore be considered when feasible. Liver Transplantation AASLD. Received November 10, 2016; accepted January 26, Liver transplantation (LT) is accepted as the best treatment modality for hepatocellular carcinoma (HCC) in patients with cirrhosis, who are simultaneously treated for both cancer and the underlying liver disease. (1-3) Abbreviations: AFP, alpha-fetoprotein; CI, confidence interval; DFS, disease-free survival; HCC, hepatocellular carcinoma; HR, hazard ratio; IQR, interquartile range; LT, liver transplantation; MS, median survival; OS, overall survival; TACE, transarterial chemoembolization; TSF, time to surgical failure. Address reprint requests to Marc-Antoine Allard, M.D., Centre Hepatobiliaire, H^opital Paul Brousse, 14 av Paul Vaillant Couturier, Villejuif, France. Telephone: ; marcantoineallard@yahoo.fr 440 ORIGINAL ARTICLE Although the selection criteria for LT in HCC patients are well established, post-lt HCC recurrence occurs in approximately 10%-20% of patients. (4,5) Post-LT relapse is considered as the most important limiting factor for longterm survival in these patients. Recurrence of HCC after LT is commonly considered as a palliative condition. Indeed, the addition of longterm immunosuppressive therapies and complex surgical history in these patients largely explain why strategies including surgery are often not considered. A few studies (6-13) have reported the impact of surgical treatment in patients with post-lt HCC recurrence, but the overall number of patients analyzed remains limited. Therefore, there is a need for further studies in this area. The aim of this study was to report a single-center experience about the recurrence of HCC after LT in

2 LIVER TRANSPLANTATION, Vol. 23, No. 4, 2017 order to identify the risk factors of survival and to analyze the impact of surgical treatment. Patients and Methods STUDY POPULATION Our study population consisted of all consecutive patients who had HCC recurrence after an LT for histologically proven HCC from January 1993 to December 2013 at the Paul Brousse Hospital, a tertiary hepatobiliary and transplantation center (Villejuif, France). The patients were selected using a prospectively maintained database of patients transplanted for HCC. Indications of LT for HCC patients have been previously detailed. (14-16) POSTTRANSPLANT IMMUNOSUPPRESSION Posttransplant immunosuppression was based on the association of an anticalcineurin (cyclosporine A at the early period, and tacrolimus for the recent period) and corticosteroids (initial dose of 5 mg/kg/day until day 7, then reduced to 0.3 mg/kg/day during the first month, then to mg a day until the third month, and then gradually decreased). Mycophenolate mofetil was given to patients with renal insufficiency or as an additional immunosuppression for those experiencing acute rejection. Mammalian target of rapamycin inhibitors were used in patients with recurrent HCC or de novo malignancies only in the last 4 years. Our immunosuppression protocol was not modified in patients with a higher risk of post-lt HCC recurrence. FOLLOW-UP After discharge, the patients were followed up at the outpatient clinics. The follow-up included ultrasound, liver test, and alpha-fetoprotein (AFP) measurements Eric Vibert consults for Nanobiotix and recieved grants from ANR Tecsan Iflow. Rene Adamisonthespeaker sbureauofmerck-seronoandsanofi- Aventis. Copyright VC 2017 by the American Association for the Study of Liver Diseases. View this article online at wileyonlinelibrary.com. DOI /lt every 3 months for 2 years. Chest and abdominal computed tomography scans were performed every 6 months for the first 2 years and then once a year thereafter. SCREENING POLICY OF RECURRENCE Suspicion of recurrence was discussed at the multidisciplinary oncological meeting. Patients with an increased AFP and a hepatic or extrahepatic mass on radiological examination showing arterial enhancement followed by subsequent washout were considered to have a recurrence; histological confirmation was obtained in the case of doubtful diagnosis. The types of recurrences were classified as follows: 1. Intrahepatic (6 extrahepatic) versus extrahepatic only. 2. Unifocal (only 1 organ is involved, but there may be several lesions) versus multifocal (disease involves at least 2 metastatic sites). MANAGEMENT OF RECURRENCE Different options were discussed, 1 patient at a time, by a multidisciplinary team including surgeons, radiologists, hepatologists, and oncologists. Resection was proposed to each patient whenever feasible from a technical point of view in the absence of progression while on systemic treatment. Systemic chemotherapy was administered in patients with multifocal disease and/or unresectable disease. The type of chemotherapy regimen changed over time. Adriamycin was used as the first-line treatment in the 1990s; this was switched for gemcitabine and oxaliplatin in the 2000s until sorafenib became available. Locoregional therapies such as transarterial chemoembolization (TACE) and/ or external radiotherapy were proposed in nonresectable patients with intrahepatic locations. STATISTICAL ANALYSIS The results for continuous variables are given as median (interquartile range [IQR]), and the results for categorical variables are given as numbers (percentage). Time survival was calculated from the date of recurrence to the date of latest news or the date of death. For disease-free survival (DFS), time was calculated from the date of resection until the date of the second recurrence. The time to surgical failure (TSF) was calculated from the date of resection until the date of ORIGINAL ARTICLE 441

3 LIVER TRANSPLANTATION, April 2017 TABLE 1. Characteristics of the Study Population Variables Value (n 5 70) Median age, years 55 (49-60) Sex, male 61 (87.1) Age 60 years 16 (22.9) Underlying disease Alcohol 11 (15.7) Hepatitis C 30 (42.9) Hepatitis B 17 (24.3) No cirrhosis 11 (15.7) Pre-LT hepatectomy 6 (8.6) Median AFP before LT, ng/ml 10 (10-50) AFP before LT 100 ng/ml 15 (21.4) Tumor characteristics at LT Median max tumor diameter, mm 40 (28-57) Median tumor number 3 (1-6) Microvascular invasion 40 (57.1) Macrovascular invasion 11 (15.7) Inside Milan criteria 23 (32.9) Post-LT recurrence AFP at relapse 100 ng/ml 16 (22.9) Median time to recurrence, months 17 (10-35) Multifocal 31 (44.3) Intrahepatic recurrence 20 (28.6) Surgical management 22 (31.4) NOTE: Data are given as n (%) or median (IQR). death or recurrence that cannot be treated with potentially curative intent, as already described. (17) Cumulative overall survival (OS) rates were calculated by using the Kaplan-Meier method, and the survival curves were compared by using the log-rank test. Multivariate analysis of risk factors associated with HCC recurrence after LT was performed using a Cox proportional hazard model. A P value < 0.15 at univariate analysis was necessary for entry in the model. The final variables were selected according to stepwise backward elimination procedure. The proportional hazards assumption of the Cox model was verified by testing the absence of correlation between Schoenfeld residuals and survival time. Calculations were done using R, version (R Foundation, Vienna, Austria). Results BASELINE CHARACTERISTICS OF THE STUDY POPULATION Of the 493 patients transplanted for HCC during the study period, a total of 70 (14.2%) patients developed a recurrence and were included in this study. The baseline clinical-pathological characteristics of patients with post-lt recurrence of HCC are summarized in Table 1. Briefly, most patients were male (n 5 64; 87.1%). The median age was 55 years (49-60 years). The most common underlying diseases were HCV-related cirrhosis (42.9%), HBV-related cirrhosis (24.3%), and alcoholic cirrhosis (15.7%). A total of 23 (32.9%) patients were within the Milan criteria. Fifteen (21.4%) patients had a serum AFP level 100 ng/ ml before LT. The median follow-up from LT was 78 months, ranging from 16 to 207 months. The median time from LT to recurrence was 17 months (10-35 months). The majority of recurrences (n 5 49; 70%) were detected within the first 2 years following LT. Notably, late recurrences (more than 5 years after LT) were observed in 6 (8.6%) patients. At the time of diagnosis, most recurrences were extrahepatic (n 5 51; 72.9%), whereas intrahepatic only and both intrahepatic-extrahepatic locations were found in 2 (2.8%) patients and 17 (24.3%) patients, respectively. The disease was unifocal in 39 (55.7%) patients. The most common extrahepatic sites for metastasis were lung, intra-abdominal lymph node, and bone. The median time to recurrence was 16 months in patients with intrahepatic recurrence versus 18 months in patients without intrahepatic recurrence (P ), whereas multifocal recurrence occurred after a median time from LT of 16 months versus 19 months for unifocal recurrence (P ). At the last follow-up, 55 patients had died. Overall, the median survival (MS) after recurrence of disease was 19 months with 1-, 3-, and 5-year OS rates of 65%, 26%, and 5%, respectively. MANAGEMENT OF POST-LT RECURRENCE Overall, 24 patients were operated on with curative intent. Of them, 2 could not be resected due to unresectable lesions found at laparotomy. Finally, 22 (31.4%) patients underwent complete resection of recurrence. A total of 6 patients were treated by TACE, whereas 20 patients received chemotherapy. Twenty-two patients did not receive chemotherapy following the diagnosis of recurrence because of contraindications due to a poor general condition. No patients were retransplanted for HCC or other pathologies. In resected patients, interventions included lung resection (n 5 7; 31.8%), lymph node resection (n 5 4; 18.2%), adrenal gland resection (n 5 4; 18.2%), parietal resection (n 5 4; 18.2%), hepatectomy (n 5 2; 9.1%), and pancreatectomy (n 5 1; 4.5%). The 90-day mortality was 0%. Severe complications (Clavien- Dindo III-IV) occurred in 4 (18.2%) patients. 442 ORIGINAL ARTICLE

4 LIVER TRANSPLANTATION, Vol. 23, No. 4, 2017 FIG. 1. Kaplan-Meier curves of postrecurrence survival: resected patients versus nonresected patients. FIG. 3. Kaplan-Meier post-lt recurrence survival among patients who recurred after surgical resection. The postrecurrence survival was much better in resected patients compared with that of nonresected patients (MS of 35 months versus 15 months, respectively; P < 0.001; Fig. 1). Even though resected patients experienced a significantly longer survival, 21 of them (95.5%) developed a second recurrence. The median time to the second recurrence was 12 months after resection (Fig. 2). A total of 11 (50.0%) patients had a single recurrence, and 10 (45.5%) developed a multifocal disease. The most common sites for the second recurrence after initial resection were lungs (n 5 11; 53.1%) and bones (n 5 9; 42.9%). FIG. 2. Kaplan-Meier curves of patients resected: DFS and survival until surgical failure. Interestingly, 8 patients underwent a second, and 4 of them underwent a third surgical procedure. The possibility of repeat resection enables increasing of TSF to 16 months (Fig. 3). Among the 21 patients with recurrence, the postrecurrence survival tended to be higher in patients who were reoperated (MS: 93 months) compared with the nonreoperated patients (MS: 28 months, P ; Fig. 3). PROGNOSTIC FACTORS OF POST-LT HCC RECURRENCE SURVIVAL: UNIVARIATE AND MULTIVARIATE ANALYSIS In univariate analysis, none of the factors related to patient characteristics or pretransplant disease were associated with postrecurrence survival. The factors with a P value < 0.10 were pre-lt AFP, AFP at recurrence, AFP > 100ng/mL before LT and recurrence (this cutoff was previously used in transplanted HCC patients), (18) multifocal disease, intrahepatic disease, time to recurrence, and nonsurgical management (Table 2). Four variables remained in the final multivariate model as independent factors of postrecurrence survival: AFP level > 100 ng/ml at relapse (hazard ratio [HR], 2.01; 95% confidence interval [CI], ; P ); intrahepatic location (HR, 1.8; 95% CI, ; P ); multifocal recurrence (HR, 1.79; 95% CI, ; P ); and resection of the recurrence (HR, 0.4; 95% CI, ; P ; Table 2). ORIGINAL ARTICLE 443

5 LIVER TRANSPLANTATION, April 2017 TABLE 2. Prognostic Factors of Post-LT Recurrence Survival: Univariate and Multivariate Analysis Univariate Analysis Multivariate Analysis 1-year OS (%) MS, months HR (95% CI) P Value HR 95% CI P Value Sex Female Male Age, years 1.01 ( ) 0.42 <60 years years Underlying disease Alcohol Hepatitis C Hepatitis B No cirrhosis Period Pretransplant HCC data Pre-LT hepatectomy No Yes Pre-LT TACE No Yes AFP before LT, ng/ml 1.00 ( ) 0.09 AFP before LT 100 ng/ml <100 ng/ml ng/ml Tumor number 1.02 ( ) 0.33 Maximal tumor size, mm 1.00 ( ) 0.59 Milan criteria Inside Outside Microvascular invasion No Yes Macrovascular invasion No Yes 39 9 Posttransplant Nonsurgical management < Surgical management Unifocal Multifocal AFP at post-lt relapse, ng/ml 1.00 ( ) <0.001 AFP at post-lt relapse <100 ng/ml ng/ml 48 9 Time to post-lt recurrence, months 0.99 ( ) 0.06 Time to post-lt recurrence <12 months months Intrahepatic reccurrence No Yes Discussion Despite continuous efforts to refine the selection criteria, (19) LT for HCC is impaired by a rate of recurrence of approximately 10%-20% that remains stable over time. The management of post-lt HCC recurrence is unclear, and the available data are limited. Herein, we provide an overview of series dealing with post-lt HCC recurrence in Table ORIGINAL ARTICLE

6 LIVER TRANSPLANTATION, Vol. 23, No. 4, 2017 Authors TABLE 3. Overview of Previous Series Reported in the Literature Number Resected/ Number Included, (%) Median Follow-up After LT, Months Median Time to Recurrence, Months First Site of Recurrence Median OS, Months* Median OS in Resected Patients, Months* Median OS in Nonresected Patients, Months* Regalia et al. (20) (1998) 7/21 (33) (1-25) Liver Schlitt et al. (13) (1999) 11/39 (28.2) ( ) Liver 19 Roayaie et al. (10) (2004) 18/57 (31.6) 12.3 ( ) Liver Kornberg et al. (9) (2010) 7/16 (43.8) (4-58) Lung Valdivieso et al. (11) (2010) 8/23 (34.8) (2-93) Lung (free 4.5 (free survival) survival) Kim et al. (21) (2011) 3/39 (7.7) 6.3 (since the 8.2 ( ) Bone moment of treatment of the recurrence) Toso et al. (8) (2013) 6/30 (20) 18.7 (after 24 (mean) Liver 18 recurrence) Sapisochin et al. (6) (2015) 38/121 (31.4) 29.5 ( ) 14 ( ) Liver 12.2 Bodzin et al. (7) (2016) 25/106 (23.6) 15.8 Lung Paul Brousse (2016) 22/70 (31.4) 78 (16-207) 17.3 Lung *Calculated from the time of recurrence. LOCATIONS AND TIME TO RECURRENCE We found that the median time to post-lt recurrence of HCC was 17 months and that 70% of recurrences were diagnosed within the 2 years following LT. These results are in accordance with other studies that reported a median time of recurrence ranging from 7 to 36 months. (6-10,21,22) In previous studies, (7,9,11) as well as in our experience, the lung is the most frequent metastatic site of relapse. This argues for close followup including thoracic imaging, particularly during the first 2 post-lt years. OVERALL PROGNOSIS Overall, post-lt HCC recurrence yields poor outcome, as already reported, with a MS of less than 2 years in most of the studies. (9,11) The MS after recurrence observed in our study is 1 of the longest reported to date, suggesting that multidisciplinary management including chemotherapy, local therapies, and surgery is effective in these patients. FACTORS ASSOCIATED WITH PROLONGED SURVIVAL Our analysis of prognostic factors showed that HCC recurrence after LT encompasses a large spectrum of different possible evolutions. The most favorable cases are represented by unifocal and extrahepatic recurrences (lung, lymph node, or parietal dissemination) with low AFP, especially when oncological resection can be achieved. On the contrary, multifocal recurrences with intrahepatic locations and elevated AFP carry a poor prognosis. The prognostic value of AFP in HCC before or after resection, and/or LT has been largely validated. (18,23) So it is not surprising that an elevated AFP at the moment of the recurrence appears as a strong predictor of poor outcome. (6,7) Notably, no pre-lt factors (clinical characteristics, histology of explant) had a prognostic value for survival after post- LT HCC recurrence. Similarly, a short interval between transplantation and recurrence did not emerge as a worse prognostic factor, which is in contrast with the previous findings. (6,7) RESULTS OF SURGERY AND REPEAT SURGERY Most of the recent studies have shown the favorable impact of management including surgery. (6,7) In a bicentric study, Sapisochin et al. (6) showed that patients treated with surgical resection or ablation experienced improved survival compared with patients who could not be resected. Proportions of resections ranged from 8% to 44% according to studies (Table 3), which likely translates the differences in the evaluation and selection of candidates for surgery across the centers. However, the resection of HCC recurrence is impaired by a high rate of recurrence. It is noteworthy that 8 patients could be reoperated again, and 4 patients could be treated with curative intent for the third time. The possibility of repeat resection was ORIGINAL ARTICLE 445

7 LIVER TRANSPLANTATION, April 2017 associated with a trend for better postrecurrence survival. Statistical significance was not obtained probably due to the limited number of patients. This finding supports a repeat surgical approach when possible. It can be argued that surgery was performed in the patients with the highest initial survival probability (good general conditions, limited disease, and no progression). Therefore, the real positive influence of surgery could be questioned. However, a prospective and randomized comparison is not feasible, given the limited number of patients eligible for surgical treatment. Moreover, propensity score based matching was not technically feasible due to the differences in the 2 groups and the size of the study population. We acknowledge that our results do not allow us to ascertain the positive influence of resection, but the fact that resection remained an independent factor of survival after post-lt HCC recurrence and that longterm survival could only be achieved in resected patients suggests that resection should be advocated whenever possible. LIMITATIONS OF THE STUDY This study is limited by its retrospective design and the limited size of the study population. Moreover, given the long study period, the systemic chemotherapies used in HCC have changed. We did not observe any difference in survival when comparing the 2 periods versus Even if sorafenib may induce response or stabilization of disease in some patients, the chance for longterm control of metastatic HCC patients remains low. (24) In conclusion, overall, the recurrence of HCC after LT is associated with poor prognosis. 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